The primary aims of this proposal are to gain a better understanding of the structural requirements for binding to myo-inositol 1-phosphatase (mIPase) and to identify one or more synthetic substrate-based inhibitors of mIPase. myo-Inositol 1-phosphatase is involved in the phosphatidylinositol signal transduction pathway and is known to be inhibited by lithium. A recent theory suggests that the mechanism of action of lithium is related to its ability to inhibit mIPase. Studies with this enzyme therefore have important implications in the treatment of manic-depressive disorder. Substrate-based mIPase inhibitors will be important in establishing the mechanism of action of lithium and may provide therapeutic alternatives to lithium in the treatment of manic-depressive disorder. One of the major limitations in the design of synthetic inhibitors of mIPase is that the present knowledge of the active site and the structural requirements for binding to this enzyme is quite limited. In this study, a series of isomeric 1,2,3-cyclohexanetriol monophosphates which are molecular simplifications of myo-inositol 1-phosphate (the natural substrate), myo-inositol 2-phosphate (a known inhibitor), and (-)-chiro-inositol 3-phosphate (a known substrate) will be synthesized and evaluated for their ability to act as substrates and /or inhibitors of mIPase. These compounds will be used to investigate which of the five hydroxyl groups in the natural substrate are essential for substrate recognition and enzyme affinity. This information can then be used to develop a model of substrate binding and to design substrate-based inhibitors of mIPase which are stereochemically less complex than the natural substrates. Initially, a series of three compounds based upon myo-inositol 1-phosphate will be synthesized and evaluated, and the results from these compounds will be used to prioritize subsequent target compounds. Regardless of the results of this initial series of compounds, the second portion of this project is aimed at the development of an inhibitor of mIPase which can be used as a lead compound for continued studies of this enzyme. The strategy to be employed here is the isosteric replacement of the labile phosphate group of a known substrate--either myo-inositol 1-phosphate or a promising 1,2,3-cyclohexanetriol monophosphate--with a stable phosphonate group. The biological evaluation of all target compounds will be performed using a previously reported enzyme assay which measures enzyme activity by determining the amount of inorganic phosphate released.